AICAR Positively Regulate Glycogen Synthase Activity and LDL Receptor Expression Through Raf-1/MEK/p42/44MAPK/p90RSK/GSK-3 Signaling Cascade

Overview

Journal Biochem Pharmacol

Specialties Biochemistry
Pharmacology

Date 2007 Oct 20

PMID 17945190

Citations 4

Authors

Hsiang-Ming Wang

Sonya Mehta

Rishipal Bansode

Wei Huang

Kamal D Mehta

Affiliations

Soon will be listed here.

Abstract

5-Aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) is a commonly used pharmacological agent to study physiological effects which are similar to those of exercise. However, signal transduction pathways by which AICAR elicits downstream effects in liver are poorly understood. We report here that AICAR not only activated AMPK but also phosphorylated/deactivated glycogen synthase kinase-3 alpha/beta (GSK-3alpha/beta) and dephophorylated/activated glycogen synthase (GS) in a time-dependent manner in human hepatoma HepG2 cells. The signal connection between AICAR and GSK-3 is indirect and involves activation of Raf-1/MEK/p42/44(MAPK)/p90(RSK) signaling cascade as pharmacologic inhibition of MEK significantly reduced phosphorylation/deactivation of GSK-3 and consequent dephosphorylation/activation of GS. Moreover, silencing the expression of p90(RSK), a substrate of p42/44(MAPK), attenuated AICAR-dependent GSK-3 phosphorylation, implicating this kinase as a key mediator of AICAR signaling to GSK-3. Furthermore, consistent with the involvement of Raf-1 kinase cascade, AICAR-induced low-density lipoprotein (LDL) receptor expression in a p42/44(MAPK)-dependent manner. Finally, AICAR requires AMPK-alpha2-dependent and -independent pathways to activate Raf-1 kinase cascade as suppression of AMPKalpha2 activity, and not of AMPKalpha1, partially blocked AICAR-dependent p42/44(MAPK) activation and GSK-3 phosphorylation/deactivation. Collectively, these results highlight Raf-1 signaling cascade as the critical mediator of AICAR action on glucose and lipid metabolism in HepG2 cells.

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References

Koistinen H, Galuska D, Chibalin A, Yang J, Zierath J, Holman G . 5-amino-imidazole carboxamide riboside increases glucose transport and cell-surface GLUT4 content in skeletal muscle from subjects with type 2 diabetes. Diabetes. 2003; 52(5):1066-72. DOI: 10.2337/diabetes.52.5.1066. View

Foretz M, Carling D, Guichard C, Ferre P, Foufelle F . AMP-activated protein kinase inhibits the glucose-activated expression of fatty acid synthase gene in rat hepatocytes. J Biol Chem. 1998; 273(24):14767-71. DOI: 10.1074/jbc.273.24.14767. View

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J . Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001; 108(8):1167-74. PMC: 209533. DOI: 10.1172/JCI13505. View

Leclerc I, Kahn A, Doiron B . The 5'-AMP-activated protein kinase inhibits the transcriptional stimulation by glucose in liver cells, acting through the glucose response complex. FEBS Lett. 1998; 431(2):180-4. DOI: 10.1016/s0014-5793(98)00745-5. View

Mehta K . Role of mitogen-activated protein kinases and protein kinase C in regulating low-density lipoprotein receptor expression. Gene Expr. 2002; 10(4):153-64. PMC: 5977515. DOI: 10.3727/000000002783992451. View

Leff T . AMP-activated protein kinase regulates gene expression by direct phosphorylation of nuclear proteins. Biochem Soc Trans. 2003; 31(Pt 1):224-7. DOI: 10.1042/bst0310224. View

Marshall C . Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell. 1995; 80(2):179-85. DOI: 10.1016/0092-8674(95)90401-8. View

Buhl E, Jessen N, Schmitz O, Pedersen S, Pedersen O, Holman G . Chronic treatment with 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside increases insulin-stimulated glucose uptake and GLUT4 translocation in rat skeletal muscles in a fiber type-specific manner. Diabetes. 2001; 50(1):12-7. DOI: 10.2337/diabetes.50.1.12. View

Anil Kumar K, Marita A . Troglitazone prevents and reverses dexamethasone induced insulin resistance on glycogen synthesis in 3T3 adipocytes. Br J Pharmacol. 2000; 130(2):351-8. PMC: 1572073. DOI: 10.1038/sj.bjp.0703313. View

10.

Iglesias M, Furler S, Cooney G, Kraegen E, Ye J . AMP-activated protein kinase activation by AICAR increases both muscle fatty acid and glucose uptake in white muscle of insulin-resistant rats in vivo. Diabetes. 2004; 53(7):1649-54. DOI: 10.2337/diabetes.53.7.1649. View

11.

Pold R, Jensen L, Jessen N, Buhl E, Schmitz O, Flyvbjerg A . Long-term AICAR administration and exercise prevents diabetes in ZDF rats. Diabetes. 2005; 54(4):928-34. DOI: 10.2337/diabetes.54.4.928. View

12.

Roach P . Control of glycogen synthase by hierarchal protein phosphorylation. FASEB J. 1990; 4(12):2961-8. View

13.

Li M, Wang X, Meintzer M, Laessig T, Birnbaum M, Heidenreich K . Cyclic AMP promotes neuronal survival by phosphorylation of glycogen synthase kinase 3beta. Mol Cell Biol. 2000; 20(24):9356-63. PMC: 102192. DOI: 10.1128/MCB.20.24.9356-9363.2000. View

14.

Armstrong J, Bonavaud S, Toole B, Yeaman S . Regulation of glycogen synthesis by amino acids in cultured human muscle cells. J Biol Chem. 2000; 276(2):952-6. DOI: 10.1074/jbc.M004812200. View

15.

Dent P, Lavoinne A, Nakielny S, Caudwell F, Watt P, Cohen P . The molecular mechanism by which insulin stimulates glycogen synthesis in mammalian skeletal muscle. Nature. 1990; 348(6299):302-8. DOI: 10.1038/348302a0. View

16.

Fang X, Yu S, Tanyi J, Lu Y, Woodgett J, Mills G . Convergence of multiple signaling cascades at glycogen synthase kinase 3: Edg receptor-mediated phosphorylation and inactivation by lysophosphatidic acid through a protein kinase C-dependent intracellular pathway. Mol Cell Biol. 2002; 22(7):2099-110. PMC: 133668. DOI: 10.1128/MCB.22.7.2099-2110.2002. View

17.

Krause U, Bertrand L, Maisin L, Rosa M, Hue L . Signalling pathways and combinatory effects of insulin and amino acids in isolated rat hepatocytes. Eur J Biochem. 2002; 269(15):3742-50. DOI: 10.1046/j.1432-1033.2002.03069.x. View

18.

Lawrence Jr J, Roach P . New insights into the role and mechanism of glycogen synthase activation by insulin. Diabetes. 1997; 46(4):541-7. DOI: 10.2337/diab.46.4.541. View

19.

Chiloeches A, Mason C, Marais R . S338 phosphorylation of Raf-1 is independent of phosphatidylinositol 3-kinase and Pak3. Mol Cell Biol. 2001; 21(7):2423-34. PMC: 86875. DOI: 10.1128/MCB.21.7.2423-2434.2001. View

20.

Corton J, Gillespie J, Hawley S, Hardie D . 5-aminoimidazole-4-carboxamide ribonucleoside. A specific method for activating AMP-activated protein kinase in intact cells?. Eur J Biochem. 1995; 229(2):558-65. DOI: 10.1111/j.1432-1033.1995.tb20498.x. View